With proper medications human immunodeficiency virus (HIV) patients now live almost full lifespans; however, HIV associated neurocognitive disorder (HAND) continues and its prevalence is increasing. This may be, in part, because HIV infection remains in the brain.
HAND is characterized by the development of cognitive, behavioral and motor abnormalities. HAND comprises a progressive pattern of CNS involvement that ranges from asymptomatic neurocognitive impairment (ANI) and minor neurocognitive disorder (MND), to the most severe HIV-associated dementia (HAD). HIV infection in the brain also leads to increased Alzheimer amyloid precursor protein (AβPP) production and susceptibility to amyloid beta (Aβ) deposition, which may induce the development of HAND. Anti-retroviral therapies (ARV) have been shown to improve cognition and reduce the prevalence of HIV-associated dementia; however, continued HIV infection and aging process exacerbate the incidence of HAND.
Role of α, β, and γ-secretases in amyloidogenesis: Deposition of extracellular Aβ plaques and intracellular Aβ and Tau neurofibrillary tangles (NFTs) are major pathological hallmarks of neurocognitive dysfunctions. Intraneuronal accumulations of Aβ and increased formation of insoluble Aβ plaques in brain continue to be implicated in the pathogenesis of various neurological disorders including Alzheimer's disease (AD) and HAND. Increased amyloidogenic metabolism of AβPP by α-secretase and γ-secretase results in the formation of soluble AβPP (sAPP), which plays a protective role in normal synaptic signaling, learning, memory, emotional behaviors, and neuronal survival. However, AβPPP can be also cleaved sequentially by β-secretase and γ-secretase to release the Aβ1-40 and Aβ1-42 which can aggregate to form plaques. Neurofibrillary tangles (NFTs), the hallmark of neurocognitive dysfunctions, are principally composed of abnormally phosphorylated Tau protein.
Recent decades have witnessed an entangled epidemic of cocaine abuse and HIV infection. Cocaine enhances the replication of HIV-1, suggesting a link between cocaine use and progression of HIV-1 infection. Cocaine also exacerbates the effect of HIV in the brain. These hypotheses are supported by a number of clinical studies, animal models, and in vitro investigations. Although clinical studies report associations between HIV and cocaine, the underlying molecular mechanisms of cocaine-induced effects in HAND remain unclear. Husebekk et al. reported elevated levels of acute phase level of serum amyloid protein A (a precursor to amyloid fibrils) in male homosexuals with acquired immune deficiency syndrome (AIDS) or AIDS-related complex. Giometto et al. reported the accumulation of Aβ precursor protein in HIV encephalitis brains. Increased prevalence of amyloid plaques was also reported in the cortex of AIDS brains compared with age-matched, non-HIV-infected controls. Subsequently, studies showed increased amyloid deposition in the brains of HIV-1-infected patients. Studies also suggest that an HIV-1 infection in the brain facilitates Aβ deposition and amyloid plaque formation which may induce the development of HAND. Liu et al. reported that peritoneal injection of cocaine in rats stimulated hyperphosphorylation of tau and neurofilament in cortex, hippocampus and caudato-putamen regions of brain.
As such, neurocognitive dysfunction is enhanced in HIV patients that are ingesting cocaine and other drugs of abuse. Cocaine causes neuronal impairments as well as increases the incidence and severity of HAND. Despite significant therapeutic advances made in the management of HIV, effective treatments against HIV infection in the brain and the pathogenesis of HAND remains a formidable task. This may be partly because of the lack of understanding of the underlying mechanisms and partly because of the inability of drugs to cross the blood brain barrier (BBB). In addition, neurological complications associated with HIV have changed over the past 30 years; clinical and pathological features of HAND have become more like Alzheimer's disease including the presence of increased brain deposition of amyloid-β (Aβ) proteins.